CONSIDERATIONS ON GENETIC AND ENVIRONMENTAL-FACTORS THAT CONTRIBUTE TO RESISTANCE OR SENSITIVITY OF MAMMALS INCLUDING HUMANS TO TOXICITY OF2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) AND RELATED-COMPOUNDS .1. GENETIC-FACTORS AFFECTING THE TOXICITY OF TCDD

The marked species differences in short-term toxicity (30-day LD50) of ca. 10,000 (LD50: guinea pigs ca. 1 mu g/kg body wt and Han/Wistar Ku opio rats more than 9600 mu g/kg body wt) of 2,3,7,8-tetrachlorodibenz o-p-dioxin (TCDD) is one of the central issues of the controversies th at have developed on the validity of risk assessment strategies for TC DD and related compounds, One of the most challenging issues that toxi cologists face today is the identification of genes that contribute to or are responsible for increased resistance or sensitivity to TCDD an d related compounds, It is assumed that most, if not all, toxic effect s of TCDD are mediated more or less through the binding affinity to th e Ah receptor, This hypothesis was extended and tries to explain the d ifferences in sensitivity/resistance of animals including humans to TC DD by their total fat (lipid) content, In this respect the gene or gen es which is or are responsible for obesity of mammals including humans are of great interest, An obvious linear positive logarithmic relatio nship between the oral 30-day LD50 (mu g/kg) of TCDD in different spec ies and strains of mammals and their total body fat content (TBF%) was found: log LD50 = 5.30 x log (TBF) - 3.22, or LD50 = 0.000603 x (TBF) (5.30), By means of this regression the toxicity of TCDD in mammals in cluding humans of different age and/or body weight can be predicted if their total body fat content is known, Examples of single-gene and po lygenic disease models in different mammals, such as nonobese diabetic , diabetic, viable yellow, obese, and fat mice, as well as transgenic mice, and other suitable animal models, such as fatty Zucker rats, Han /Wistar (Kuopio) rats, and minipigs, are discussed, and predicted LD50 values of TCDD in these animals and humans are presented. (C) 1997 Ac ademic Press.